Skin is exposed to damage resulting from various sources, including both environmental factors and biochemical processes. Oxidative processes damage proteins, lipids, and other cellular components necessary to maintain the health and appearance of skin, resulting in skin changes, such as skin aging, hyperpigmentation, UV damage, lines, wrinkles, uneven skin texture, etc.
Skin aging is accompanied by a number of morphophysiological changes which are described in the literature. See, e.g., Gilchrest, B. A. J. Cutaneous Aging Cosmet. Dermatol. 1988, 1, 1-3, and Arch. Dermatol. 1979, 115, 1343-1346. At the physiological level, skin aging is accompanied by a decrease in at least one critical skin function, such as epidermal turnover, healing, clearance of chemicals from the dermis, water regulation, sensory perception, mechanical protection, immunocompetence, vascular reactivity, blood flow, sweat gland function, turgor, sebum production or Vitamin D synthesis.
At the morphological level, a decline in critical physiological functioning is associated with a loss in the normal pattern of corneocyte desquamation, epidermal thinning, and/or the presence of atypical epidermal cells. Other characteristics include a reduction in the height of rete ridges along with a corresponding effacement of dermal papillae, a general weakening of the derma-epidermal junction, excessive accumulation of elastin, and a loss of collagen and other ground substances, a decrease in dermal volume (turgor), pigmentary disorders, attrition of capillary vessels, chronic inflammation and the occurrence of benign, and/or malignant tumors. Some of the clinical manifestations of these morphological changes which are relevant to cosmetic appearance and dermal health include a rough, flaky and/or dry skin surface, itching, excessive wrinkling, sagging, loss of elasticity, sallow color, mottled pigmentation, thinning hair, nail brittleness and, in some cases, skin growths.
The etiological bases underlying skin aging are only partially understood. But, it is recognized that the effect of ultraviolet light (UVL), especially from the sun, constitutes a significant factor in the acceleration of skin aging. Several studies have shown that skin which has been exposed to sunlight undergoes aging sooner than unexposed areas in the same individual. By comparing the histological and functional characteristics of exposed and unexposed skin, investigators have observed differences between chronological and accelerated premature aging. See, e.g., Montagna, W. J. Inves. Dermatol. 1979, 73, 47-53; Gilchrest, B. A. J. Invest. Dermatol. 1983, 80, 81s-85s; and Gilchrest, B. A. J. Invest. Dermatol. 1979, 73, 59-66.
The UVL component of sunlight is responsible for triggering molecular changes that damage biological tissues including the skin. One known mechanism for sun-induced aging results from the generation of free radicals in the skin. One proposed pathway to free radical generation, the so-called Haber-Weiss reaction (shown in Scheme I), is a chemical pathway which generates the most reactive free radical species, the hydroxy radical.

In Scheme I, O2.− is singlet oxygen or the superoxide ion, HO2. is the hydroperoxyl radical, H2O2 is hydrogen peroxide, HO. the hydroxy radical, and H2O is water. In the Haber-Weiss reaction, electrons (e−) are gained through the oxidation of metals such as iron, copper, and zinc, which are typically present in and on the skin. The hydrogen atoms are gained through the destructive oxidation of biological molecules essential to the normal function of cells, tissues, and organs, such as lipids, proteins, DNA, RNA, and enzymatic cofactors. There are numerous studies showing how the oxidation of these essential biological molecules is detrimental to the skin, in both the long term and short term.
The retinoids are biologically active compounds involved in essential functions such as vision, embryonic development and the growth and maintenance of normal skin. The art teaches that topical application of skin preparations containing retinoids provides a significant improvement in clinical appearance. See, e.g., U.S. Pat. Nos. 4,603,146 and 4,877,805. Additionally, topical application of retinoids provide improvement with respect to several histological parameters, such as thickening of the epidermis including the stratum granulosum, an increase in the height of rete ridges and the number of dermal papillae, a gradual displacement of age-related deposition of dermal elastin by collagen and peptidoaminoglycans, normalization of melanocyte function, and an increase in the number of dermal fibroblasts. See, e.g., Zelickson, A. S. J. Cutaneous Aging Cosmet. Dermatol. 1988, 1, 41-47; Weiss, J. S. JAMA, 1988, 259, 527-532; Bhawan J. Arch. Dermatol. 1991, 127, 666-672; and Kligman, L. H. Connect. Tissue Res. 1984, 12, 139-150. U.S. Pat. No. 4,603,146 also describes the use of Vitamin A acid for retarding skin aging, and U.S. Pat. No. 4,877,805 describes the use of retinoids generally for the same purpose. U.S. Pat. No. 5,747,051 describes the use of a retinyl ester for treating a skin condition, though the ester is a simple, single reverse ester compound, such as retinyl palmitate, retinyl acetate, or retinyl propionate, not a double ester or a compound having two or more linking moieties.
The skin is a target for and requires retinoids. This conclusion stems from the fact that Vitamin A deficiencies lead to skin lesions. Additionally, skin cells, such as fibroblasts and keratinocytes, contain high-affinity cytosolic receptors for retinoids, thus further demonstrating the target nature of these skin cells.
It is well-known that therapeutic doses of topically applied retinoids frequently cause skin irritations which interfere with treatment. To solve this problem, the art has resorted to conjugating retinoids with glucuronic acid, among other methods (e.g., microsponge delivery systems or liposomes). See, e.g., U.S. Pat. No. 4,855,463, which discloses water-soluble glucuronic acid derivatives of Vitamin A for improved metabolic uptake; and Chen, S. J. Invest. Dermatol. 1992, 98, 560 (Abstract), which describes conjugates of retinoids and acetaminophen. In both cases, conjugation was achieved by attaching the other molecule to carbon-15 of the retinol structure.
U.S. Pat. No. 4,216,224 describes retinyl esters of hydroxy acids, hydroxy amides, or hydroxy acid esters for use in treating psoriasis. U.S. Pat. No. 5,124,356 describes ester and amide conjugates of trans-retinoids, although the molecule conjugated with the retinoid is not described as providing any separate therapeutic benefit. EP 0 391 033 A2 further describes the preparation of retinal derivatives, especially acetals and hemiacetals, useful in treating a variety of skin conditions.
JP S63-66160 A (1988) describes the preparation of a retinoyl ester of 1-ascorbic acid which is taught to be useful for increasing the activity of blood vessel endotheliocyte plasminogen activators, and for increasing the hydrophilic properties of retinol and retinoic acid to reduce instability of the composition due to oxidation. In vitro data on endotheliocyte cultures showed increased activity of plasminogen activator, but no methods or compositions for administration are disclosed.
JP H04-210686 A (1992) describes a method for the manufacture of tocopheryl retinoate. This compound is taught to be useful for treating skin ulcers (e.g., JP S61-207332 A) and for preventing the roughening of skin (e.g., JP S51-73137 A). U.S. Pat. No. 5,182,396 discloses that 1-hydroxy Vitamin D esters with Vitamin A acid are useful for treating cutaneous ulcers and tumors.
Carboxylic acids are also useful in the treatment of aging skin, especially alpha- and beta-hydroxy acids and ketoacids. These are generally referred to as AHAs (Alpha Hydroxy Acids). See, e.g., U.S. Pat. Nos. 3,920,835, 4,045,559, 4,053,630, 4,363,815, and 5,652,266. Additionally, U.S. Pat. No. 4,194,007 describes α-hydroxyretinoic acid and α-ketoretinoic acid as derivatives of retinoic acid.
These AHAs improve the clinical appearance and mechanical properties of aging skin. A normalization in the pattern of epidermal keratinization and a reduction in the cohesive forces acting between keratinocytes and corneocytes have also been reported after treatment with AHAs (Van Scott, E. J. J. Acad. Dermatol. 1984, 11, 867-879). Other investigators have observed such benefits as wrinkle reduction after topical application of AHAs. They postulate that AHAs stimulate collagen and glycosaminoglycan synthesis by cultured fibroblasts (Dial, F. D. Cosmetic Dermatology, 1990, 5, 32-34). AHAs also increase the production of collagen and peptidoaminoglycans (Lavker, R. M. J. Am. Acad. Dermatol. 1992, 26, 535-544), thereby further improving the general topographical appearance and viscoelastic behavior of skin.
The action by which AHAs improve the clinical appearance and mechanical properties of skin is not thoroughly understood. One feature of aging skin is hyperkeratinization, a condition in which the corneocytes adhere in excess, thereby creating a thickened stratum corneum and a dry appearance. The forces responsible for the adhesion of corneocytes are non-covalent in nature and evidence exists that both ionic and hydrophobic interactions are involved. In the case of ionic interactions, calcium ions are believed to bridge adjacent corneocytes by forming complexation bonds between cholesteryl sulfate residues that are firmly anchored to the corneocyte cell wall (Shapiro, L. J. Lancet 1978, 1, 70-72).
Since ionic interactions are pH dependent, AHAs may decrease corneocyte cohesion by temporarily opening up calcium bridges. However, an explanation of activity based on pH alone is not satisfactory. Earlier work aimed at studying the relationship between the chemical structure of these agents and their ability to influence the viscoelastic behavior of the stratum corneum clearly indicates that, among the series of AHAs studied, those having hydroxy groups in the alpha position consistently lowered this parameter (Takahashi, M.; Machida, Y., J. Soc. Cosmet. Chem. 1985, 36, 177-187). The lower the viscoelastic modulus, the less force is required to cause deformation (i.e., the softer the stratum corneum).
AHAs are known to produce a long-lasting decrease in the elastic modulus of skin. This means softening and, with regular use, a normalization in the pattern of corneocyte desquamation. Certain beneficial effects have been shown for AHAs conjugated with linear aliphatic chains having eight to ten carbons. See, e.g., Hagan, D. B., et al., “A study of the structure-activity relationships present in skin active agents” Int'l J. Cosmetic Sci. 1993, 15, 163-173.
After topical application of an AHA, skin surface pH is temporarily lowered from a normal level of about 5 to a more acidic level of about 3. The localized acidity can result in stinging, particularly on the face where microfissures are more common than on other parts of the body. Charged molecules, such as AHAs, are known to be poor skin penetrators because, ordinarily, they cannot partition and diffuse through the lipid-rich lamellae present in the intercorneocyte spaces. Because charged molecules penetrate the cutaneous barrier very slowly, it may require several hours for the increased surface acidity to be neutralized, which would end the stinging and discomfort to the patient. U.S. Pat. No. 5,605,933 describes that conjugation of a short chain carboxylic acid with a retinoid, can reduce the acidity of residue, but admits that problems relating to irritation, stability, toxicity, and dermal penetration still exist.
The present inventor has found that the formation of a double conjugate unexpectedly improves the moderation of the acidity of known retinoid compounds, including single conjugates. The novel double conjugates of this invention provide an unexpectedly superior treatment by improving AHA rates of percutaneous absorption, improving passage of double conjugates through the intact domains of the stratum corneum, and alleviating acidification of the skin and the accompanying stinging and other discomfort, even when applied to the facial area. By doubly conjugating the retinoid-AHA with a further moiety, e.g., alcohol or acyl group, the problem of skin irritation is unexpectedly significantly addressed.
It will be appreciated that a range of compounds have been considered for the treatment of numerous skin conditions including, inter alia, skin aging, acne, dryness, photodamage, and hyperpigmentation.